1 Centre for Research in Neurodegenerative Diseases, University of Toronto,Toronto, Canada2 Department of Laboratory Medicine and Pathobiology, University of Toronto,Toronto, Canada3 Department of Pathology, School of Medicine, Case Western ReserveUniversity, Cleveland, OH, USA4 McLaughlin Research Institute, Great Falls, MT, USA5 Department of Medical Biophysics, University of Toronto, Toronto, Canada6 Department of Medicine, University of Toronto, Toronto, Canada7 Centre for Prions and Protein Folding Diseases, University of Alberta,Alberta, Canada

Received 6 March 2007; Accepted 24 July 2007; Published online 16 August2007.

Abstract

The cellular prion protein, PrPC, is neuroprotective in a number of settingsand in particular prevents cerebellar degeneration mediated by CNS-expressedDoppel or internally deleted PrP ('PrP'). This paradigm has facilitatedmapping of activity determinants in PrPC and implicated a cryptic PrPC-likeprotein, ''. Shadoo (Sho) is a hypothetical GPI-anchored protein encoded bythe Sprn gene, exhibiting homology and domain organization similar to theN-terminus of PrP. Here we demonstrate Sprn expression and Sho protein inthe adult CNS. Sho expression overlaps PrPC, but is low in cerebellargranular neurons (CGNs) containing PrPC and high in PrPC-deficient dendriticprocesses. In Prnp0/0 CGNs, Sho transgenes were PrPC-like in their abilityto counteract neurotoxic effects of either Doppel or PrP. Additionally,prion-infected mice exhibit a dramatic reduction in endogenous Sho protein.Sho is a candidate for , and since it engenders a PrPC-like neuroprotectiveactivity, compromised neuroprotective activity resulting from reduced levelsmay exacerbate damage in prion infections. Sho may prove useful indeciphering several unresolved facets of prion biology.

New prion protein discovered by Canadian scientists may offer insight intomad cow disease

Scientists have discovered a new protein that may offer fresh insights intobrain function in mad cow disease. “Our team has defined a second prionprotein called ‘Shadoo’, that exists in addition to the well-known prionprotein called ‘PrP’ ” said Professor David Westaway, director of the Centrefor Prions and Protein Folding Diseases at the University of Alberta.

“For decades we believed PrP was a unique nerve protein that folded into anabnormal shape and caused prion disease: end of story. This view is nolonger accurate,” Westaway adds.

The study was conducted jointly by the University of Toronto, University ofAlberta, Case Western Reserve University (Ohio) and the McLaughlin ResearchInstitute (Montana). The research is published today in the EMBO Journal andrepresents a culmination of work initiated at the University of Toronto in1999, and then continued more recently at the University of Alberta.

This is the first discovery since 1985 of a new brain prion protein. “Asecond prion protein had been inferred by other research, based on indirectstudies and the examination of DNA sequences,” said lead author Joel Watts,a graduate student at the University of Toronto’s Centre for Research inNeurodegenerative Diseases. “But we not only demonstrate that thistheoretical protein really exists and shares several properties with healthyPrP; we have also defined an unexpected alteration in prion infections.

“As the PrP molecule alters shape and accumulates in a prion-affected brain,the Shadoo protein seems to disappear,” Watts added. Since proteins in aliving cell are the molecules “that do the work, this is likely to besignificant,” he said.

“Many facets of a prion disease like BSE are puzzling,” Westaway said. “Thepuzzles include the cause of death of brain cells, the function of normalprion proteins, and the rules governing emergence and spread of prions fromanimal to animal. We believe the Shadoo protein can give us a fresh purchaseon these important questions.”

###This research project was funded by the Canadian Institutes of HealthResearch (CIHR) and the Natural Sciences and Engineering Research Council(NSERC).

For more information, please contact:Professor David WestawayCentre for Prions and Protein Folding DiseasesLink: www.prioncentre.caUniversity of Alberta780-492-9024David.westaway@ualberta.ca

Joel Watts BScCentre for Research in Neurodegenerative DiseasesLink: http://www.utoronto.ca/crnd/University of Toronto416-978-3408Joel.watts@utoronto.ca